**3. In the beginning**

*God blessed them and said to them, "Be fruitful and increase in number; fill the earth and subdue it."*

*Genesis 1:28.*

## **3.1 The delicate hormonal axis in women and the relationship with autoimmunity: when despite the intention something is not right!**

Sex hormones are actors of great importance for the maintenance of the existing balance in the immune system. These hormones (estrogens and progesterone) and

with them prolactin have many effects on cellular and humoral immunity and on various processes together. Clinical experience has shown that some changes in this delicate hormonal balance can contribute to a greater or lesser activity of SLE, such as the use of exogenous estrogens (oral contraceptives or postmenopausal hormone therapy), and hormonal changes where there is an increased secretion of endogenous estrogens such as those associated with pregnancy.

In reproductive pshysiology that leads to the successful implantation of the embryo, with the necessary protection against immune rejection due to being a semi-allograft and at the same time maintaining close control of the immune system and adequate response of the same during pregnancy and childbirth [9]. To achieve this goal, an arsenal of inflammatory mediators is needed, and for this reason, it is logical that many of the inflammatory or immune responses have the female sex steroids as protagonists: estrogen, progesterone, and prolactin (**Figure 1**).

It has been found that there are estrogen receptors (α and β) that are essential for estrogen to act, and antibodies against these receptors, especially anti-Erα, have been detected in patients with SLE. These caused the induction of cell activation and apoptosis in lymphocytes and are closely related to the induction and maintenance of T-cell anergy and immune self-tolerance [10, 11].

One study analyzed the presence of specific antibodies against estrogens in patients with SLE. It was observed that in 45% of the patients studied these antibodies were found and induced cell activation and subsequent apoptosis in lymphocytes. There is a theory of the existence of an extracellular binding domain where these antibodies enter the cell and associate in some unknown way with the cell membrane, initiating the activation of the ERK/MAPK pathway when this is very important for selection, differentiation, and maturation of T cells and modulates their induction, their anergic quality, and self-tolerance. These antibodies could induce cell apoptosis and repeatedly alter cell-cycle control and modulation in T lymphocytes [12].
